Progressive systemic sclerosis

Richard M Keating MD (Dr. Keating of Scripps Clinic/Scripps Green Hospital has no relevant financial relationships to disclose.)
Kavitta B Allem MD (Dr. Allem of Scripps Clinic has no relevant financial relationships to disclose.)
Raymond P Roos MD, editor. (Dr. Roos of the University of Chicago owns stock in Amgen, Best Doctors, Express Scripts, Ionis, and Merck.)
Originally released April 1, 1997; last updated January 25, 2017; expires January 25, 2020

This article includes discussion of progressive systemic sclerosis, diffuse scleroderma, PSS, SSc, systemic sclerosis, systemic scleroderma, limited scleroderma, localized scleroderma, and scleroderma "en coup de sabre." The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

In 1945 Goetz, emphasizing the widespread and generally worsening visceral involvement seen in some individuals with scleroderma, proposed the term “progressive systemic sclerosis.” Today we recognize that progressive systemic sclerosis, a whole body disease, can have both diffuse cutaneous involvement and limited cutaneous involvement. Either form has the potential to cause major morbidity. Progressive systemic sclerosis occurs more frequently in females, especially during the peak incidence years of 30 to 55, where the female-to-male ratio may be as high as 12 to 1. Major mechanisms accounting for the pathological changes in progressive systemic sclerosis include generalized fibrosis, systemic microangiopathy, and immunoregulatory abnormalities. Pain symptoms are common in patients with systemic sclerosis and are independently associated with more frequent episodes of Raynaud phenomenon, active ulcers, and worsening synovitis. Among the various concepts entertained for the pathophysiology of scleroderma, the role of hypoxia, cellular stress, and a concert of interacting cytokines has been highlighted. Tyrosine kinases are involved in transforming growth factor-beta and platelet-derived growth factor, which play a central role in the pathophysiology of systemic sclerosis. Clear understanding of these mechanisms might pave the way for novel therapies for systemic sclerosis.

Historical note and terminology

The earliest description of scleroderma (skleros, hard; derma, skin) may have been made by Hippocrates around 400 BCE (Aphorism V:71). He noted, "In those persons in whom the skin is stretched, parched, and hard, the disease terminates without sweats." More definitive, early descriptions are attributed to Curzio (1753) (Seibold 1994), Chowne (1842), Startin (1846), and Gintrac (1847), who suggested the descriptive term sclerodermie (Benedek 1997). In 1863 Raynaud commented on the occurrence of peripheral vasospastic events in an individual with scleroderma. Reports of occasional visceral (lung, kidney, gastrointestinal, and cardiac) involvement in some cases of scleroderma were made in the late 1800s and early 1900s. In 1942 Thomas noted the association of calcinosis, Raynaud phenomenon, esophageal dysfunction, and telangiectasias in an individual with scleroderma. Later, in 1964 Winterbauer applied the CRST (CREST) acronym to this limited cutaneous syndrome. After it became clear that patients with CRST also had esophageal dysmotility, Velayos and colleagues added E, thus, coining the modern day term CREST (Steen 2008). CREST is an acronym for calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias. Recognized subsets of scleroderma include: diffuse systemic sclerosis, limited cutaneous systemic sclerosis, limited, localized (morphea and linear scleroderma), overlap syndromes, and undefined connective tissue disease (Wigley 1997; Mayes 1998). Formal classification criteria for systemic sclerosis were put forth by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) in 2013. The classification system is based on a scoring system with different weight given to various clinical features and the presence of antibodies associated with scleroderma. Important exclusion criteria include patients who have scleroderma-like disorders or patients with skin thickening that spares the fingers. Skin thickening of the fingers of both hands extending proximally to the metacarpal phalangeal joints carries the most weight in the classification criteria. Other clinical criteria include skin thickening of the fingers only, fingertip lesions, telangiectasia, abnormal nailfold capillaries, pulmonary arterial hypertension or interstitial lung disease, and Raynaud phenomenon. Serologic antibodies account for only one numerical score given for anti-centromere, anti-topoisomerase I (anti-Scl 70), and anti-RNA polymerase III (van de Hoogenet al 2013).

Table 1. ACR/EULAR Criteria for the Classification of Systemic Sclerosis

Item

Sub-item

Weight/Score

Skin thickening of the fingers of both hands extending proximal to the metacarpal phalangeal joints

 

9

Skin thickening of the fingers (only count the higher score)

• Puffy fingers
• Sclerodactyly of the fingers (distal to the MCP joints but proximal to the PIP joints)

2
4

Fingertip lesions (only count the higher score)

• Distal tip ulcers
• Fingertip pitting ulcers

2
3

Telangiectasia

 

2

Abnormal nailfold capillaries

 

2

Pulmonary arterial hypertension and/or ILD (maximum score 2)

• Pulmonary arterial hypertension
• ILD

2

2

Raynaud's phenomenon

 

3

SSc-related autoantibodies (anti-centromere, anti-topoisomerase I (anti-Scl-70), anti-RNA polymerase III (maximum score 3)

• Anticentromere
• Anti-topoisomerase I
• Anti-RNA polymerase III

3

Patients with a total score of 9 or higher are classified as having definite systemic sclerosis.

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